Imatinib mesylate which is N-{5-[4-(4-methylpiperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl) 2-pyrimidine-amine, having the formula given above is approved under the trademark “Gleevec®” by the US Food and Drug Administration for the treatment of Chronic Myelogenous Leukemia before and after the failure of interferon alpha. It has also been approved for the treatment of patients with kit (CD117) positive unresectable and/or metastatic malignant Gastro Intestinal Stromal Tumors (GISTs). Recently it has been approved for the treatment of pediatric patients with Philadelphia chromosome positive (Ph+) Chronic Myeloid Leukemia (CML) in chronic phase. It is known that Imatinib mesylate exists in two polymorphic forms α and β (WO 99/03854).
In the said WO application it has been sated that the α form prepared is needle shaped and is hygroscopic. It has also been stated that in this form the crystals are not well suited for pharmaceutical formulations as solid dosage from because their physical properties for example, their flow characteristics are unfavorable. The applicants have also mentioned that under certain conditions however, it is possible to obtain a crystal form which is not needle shaped. This form, in the above patent is named as βform.
From the above given description regarding the α form it is very clear that the α form of Imatinib mesylate is not suitable for preparing formulations due to its: unsuitable physical characteristics and the form which is used is only the β form.
The said WO application also describes processes for the preparation of both the forms of Imatinib Mesylate. In the Examples 1 to 3 of the said patent the process for the preparation of Imatinib mesylate β-form has described using a maximum of 50 gms Imatinib base in solution.
In the Example-2 of the said patent a process has been described for the preparation of the β-form which involves suspending Imatinib base in methanol, adding methane sulfonic acid in methanol, heating to 50° C., followed by carbon treatment and distilling off methanol. Then dissolving the residue in minimum methanol and inoculation by some seeding crystals of Imatinib mesylate β-form.
The said WO application also describes processes for the preparation of both the forms of Imatinib Mesylate In the Example-1 of the said WTO application, the α-crystal form is prepared as follows:
Imatinib base was suspended in ethanol, methane sulfonic acid was added and heated under reflux for 20 minutes and than filtered at 65° C. The filtrate was evaporated down to 50% and the residue filtered off at 25° C. (filter material A). The mother liquor was evaporated to dryness. The residue and filter material A were suspended in ethanol dissolved under reflux with addition of water. Cooling overnight to 25° C., filtration and drying yielded Imatinib mesylate α-crystal form.
The above process for preparing α-crystal form suffers from the following disadvantages    a) In Examples 2 and 3 seed crystals of β-form are required to crystallize out the product    b) The process for preparing α-crystal form given under Example-1 is not reproducible. Repetition of the experiment exactly under identical conditions as reported in the above patent (WO 99/03854) resulted only in the α-form    c) Thus, there is currently no available process to prepare the α-crystal modification.
Important solid state properties of a pharmaceutical substance are its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patients stomach fluid may have therapeutic consequences because it imposes an upper limit on the rate at which an orally-administered active ingredient may reach the blood stream. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorph form of a substance. The polymorphic form may give rise to thermal behavior different form that of the amorphous material (or) another polymorphic form.
Thermal behaviour is measured in the laboratory by such techniques as capillary melting point, Thermo Gravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC), and may be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct properties that may be detectable by X-Ray Powder Diffraction (XRPD) solid state 13CNMR spectrometry and infrared spectrometry.
The various characteristics and properties of the polymorphic forms of a substance. e.g. shape, colour, density and the like, will make one polymorphic form preferable over the others for production and/or pharmaceutical compounding. As a result, a very first step in the processes of product development of a new pharmaceutical agent is the determination of whether it exists in polymorphic forms and if so which of such form possesses advantages for the eventual commercial pharmaceutical application. In the case of Imatinib mesylate, β form is offered commercially under the trade name Gleevec®/Glivec®.
In the patent mentioned above (WO 99/03854), β-form was selected over α-form based on the following observations and conclusions.    (i) β-form is thermodynamically stable at room temperature and at temperatures below 140° C. Greater stability of the β form is thus expected.    (ii) (β-crystal form is less hygroscopic than the α-crystal form.    (iii) α-crystal form is meta stable at room temperature    (iv) β-crystal has the advantage that its flow properties are substantially more favourable than those of that the α-crystal form.
Based on the above information, we undertook a detailed study of the solid state physical properties of the polymorphic forms of Imatinib mesylate. The presumption was that these properties may be influenced by controlling the conditions under which Imatinib mesylate is obtained in solid form.
Our detailed studies by carrying out research and development work on polymorphic forms of Imatinib Mesylate, and their processes for preparation surprisingly revealed the existence of another novel, stable polymorphic form of imatinib mesylate which we have designated as α2 form, having the below mentioned characteristics.
The novel α2 form of the present invention, can be prepared under certain specific conditions with improved physical properties such as greater stability and less hygroscopicity etc thereby making it suitable just like the β-form for commercial pharmaceutical applications.
Accordingly, we focussed our R&D efforts in taking up an elaborate study on the polymorphism of Imatinib Mesylate with particular reference to stable forms. Our detailed studies of the novel α2 form revealed that:    i. The novel α2-form is not meta stable and is stable at room temperature and even at higher temperatures like 120° C.    ii. The novel α2-form is stable at normal and accelerated stress conditions both in bulk and formulated capsule form.    iii. The novel α2-form is as freely soluble in water as is the β-form. The rate of dissolution of the α2-form in the formulation is comparable and even better than that of the β-form.    iv. The flow properties of the formulations prepared with the α2 form and β-forms are comparable as the same excipient composition is employed in both cases.
The above mentioned stable α2 form of imatinib Mesylate is not hither to known and is a novel polymorphic form. In addition, the form prepared by us now is also suitable for developing a pharmaceutical composition. Such a pharmaceutical composition containing α2 form is also not known and is novel.
Therefore, the main objective of the present invention is to provide a novel α2 crystalline form of Imatinib Mesylate which is stable at room temperature and even at higher temperatures like 120° C. and accelerated stress conditions, freely soluble in water and having the characteristics given in Table 1 given below
Another objective of the present invention is to provide a process for the preparation of novel α2 form of Imatinib Mesylate which is stable and less hygroscopic and water soluble having the characteristics given in Table 1
Yet another objective of the present invention is to provide a pharmaceutical composition useful for the treatment of Chronic Myeloid Leukemia containing the novel α2 form of Imatinib Mesylate which is stable and less hygroscopic and water soluble having the characteristics given in table 1.
Still another objective of the present invention is to provide an improved process for the preparation of β-polymorphic Imatinib mesylate.
Accordingly, the present invention provides a novel α2 crystalline form of Imatinib Mesylate which is stable at room temperature and even at higher temperatures up to 120° C. and accelerated stress conditions, freely soluble in water having the XRD characteristics given in the Table-I below.
TABLE IAngle[2-d-valueTheta]AngstromIntensity %4.84118.2405733.610.4108.49070100.011.1947.8977514.211.8567.4582719.912.8816.867096.813.8196.4032812.914.8605.9566367.716.4395.3878832.417.0495.196655.617.6235.0287058.618.0524.9100061.618.5674.7749198.819.0324.6592570.219.7724.4865715.321.2364.1805560.821.5824.1143159.422.5943.9321719.723.1373.8411221.823.6963.7517225.024.8513.5799358.626.2503.392269.127.3413.2593218.728.4753.1320442.431.8962.803479.032.5332.750056.643.4472.081176.4
According to another embodiment of the present invention there is provided a process for the preparation novel α2 crystalline form of Imatinib Mesylate which is stable at room temperature and even at higher temperatures like 120° C. and accelerated stress conditions, freely soluble in water and having the characteristics given in Table 1 which comprises suspending Imatinib base in isopropanol and adding methane sulfonic acid at room temperature and maintaining the reaction mixture at a temperature in the range of 40-80° C., for a period in the range of 20-30 minutes, cooling and filtering to obtain the α2 crystal form.
According to yet another embodiment of the invention there is provided another process for the preparation of novel α2 crystalline form of Imatinib Mesylate which comprises converting Imatinib mesylate β-polymorphic modification which comprises suspending β-polymorphic it in water and organic solvents like methanol, Isopropyl ether, toluene, cyclohexane and Isopropyl alcohol, distilling off water azeotropically and, cooling filtering to obtain the α2 crystal form.
According to stiff another embodiment of the present invention, there is provided a pharmaceutical composition useful for the treatment of Chronic Myeloid Leukemia which comprises novel α2 form of Imatinib Mesylate which is stable and less hygroscopic and water soluble having the characteristics given in table 1 and a commonly employed pharmaceutically acceptable excipients.
According to another embodiment of the present invention there is provided an improved process for the preparation of β-polymorphic form of Imatinib mesylate which comprises suspending Imatinib base in a solvent selected from acetone, acetonitrile, mixture of methanol and isopropanol and mixture of isopropanol and water and adding methane sulfonic acid to the resulting solution at room temperature and maintaining the solution at the reflux temperature of the solvent (or) at room temperature and filtering the β-crystal form.
It is to be noted that the α2 form of Imatinib mesylate prepared by the process of the present invention does not substantially convert over time to form β, either as such in bulk form or after formulation in the dosage form, upon storage at about 40° and about 75% relative humidity for at least about 6 months.
Determination of presence of imatinib mesylate form-β in Imatinib mesylate α2-form prepared by the process of the present invention may be made by analysis for the presence of various peaks associated with form-β particularly at 9.7, 13.9, 18.2, 20.0, 20.6, 21.1, 22.1, 22.7, 23.8, 29.8, 30.8±0.2 degree 2θ. (WO99/03854).
FIG. 1 of the drawings accompanying these specifications shows the X-Ray Powder Diffraction (XRPD) pattern which substantially depicts a typically pure sample of Imatinib Mesylate of α2-form prepared by the process disclosed in the Example-1 given below. The 2θ values and intensities are tabulated in Table-1.
The other figures correspond to the data as detailed below:—
FIG. - 1XRD spectrum of the novel α2 formFIG. - 2IR spectrum of the novel α2 formFIG. - 3DSC thermogram of the novel α2 formFIG. - 4XRD spectrum of the novel α2 form capsules stored for6 months at 40° ± 2°/75 ± 5% (Table-5)FIG. - 5XRD spectrum of β form prepared by he process of theinventionFIG. - 6XRD spectrum of β form form prepared by he process ofthe inventionFIG. - 7XRD spectrum of β form form prepared by he process ofthe inventionFIG. - 8XRD spectrum of β form form prepared by he process ofthe invention
The dosage form of the formulation containing the novel, stable α2 form prepared by the process of the present invention, preferably oral dosage form, may be a capsule containing the composition preferably a powdered on granulated solid composition, within either a hard (or) soft shell. The shell may be made from gelatine and optionally contains a plasticizer such as glycerin and sorbitol and an opacifying agent (or) colorant.
Methods known in the art, may be used to prepare the pharmaceutical composition containing Imatinib mesylate α2 form in the form of capsules. The excipients which may be employed include micro crystalline cellulose, lactose, crospovidone XL, colloidal silicondioxide magnesium stearate and talc
Table-2 shows suitable ranges of active ingredients and excipients (weight %) and the preferred amounts for the present pharmaceutical formulations.
TABLE 2Pharmaceutical compositions containing Imatinib Mesylate α2-formRange of %compositionPreferred %S. No.Material(w/w)compositionFunction1.Imatinib mesylate45-60%53Activeα2-formingredient2.Micro crystalline15-25%21Filler andcellulosedisintegrant3.Lactose10-20%13Diluent4.Crospovidone XL 5-10%8.7Disintegrant5.Magnesium stearate1-2%1.3Lubricant6.Talc0.5-1.0%0.80Glidant7.Colloidal Silicon1.5-2.5%2.20Glidantdioxide
Table-3 shows two typical examples of the capsule formulation containing Imatinib Mesylate α2-form and their dissolution and stability characteristics.
TABLE 3PHARMACEUTICAL COMPOSITIONS CONTAININGIMATINIB MESYLATE α2-FORMDissolution and stability characteristicsComposition (%)Composition (%)MaterialB. No. 001B. No. 002Imatinib mesylate α2-form5053Microcrystalline cellulose2521Lactose1213Crosporidone XL68.7Magnesium stearate1.51.3Tale0.50.80Colloidal silicon dioxide2.02.2Dissolution rate85% (10 min)85% (10 min)90% (20 min)90% (20 min)100% (45 min) 100% (45 min) Stability1. stable at1. stable at40° ± 2° C. and40° ± 2° C. and75 ± 5% RH75 ± 5% RH2. stable at2. stable at25° ± 2° C. and25° ± 2° C. and60 ± 5% RH60 ± 5% RH
Inference: Two typical batch formulations of Imatinib α2-form are prepared. The dissolution and stability characteristics indicate that α2-form has excellent formulation characteristics.
Table-4 shows the heat stability of α2 form over the temperature range 110-120° C. The α2 form is shown to be non-metastable and stable when heated at 120° C. for 6 hours.
Stability of α2-Crystal Form
Pure α2-crystal polymorph 1 gm prepared by the process described in Example 1 was taken in a boiling test tube and heated gradually in oil bath the substance was examined by XRPD. The results are tabulated below
TABLE 4PolymorphTime ofPolymorphcontent*heatingform detected*before hatingTemperature(hours)after heatingα2 form110° C.2α2 formα2 form110° C.4α2 formα2 form120° C.2α2 formα2 form120° C.4α2 formα2 form120° C.6α2 form*The presence of form-β was below the detection level in these examples.
Inference: The α2 form of Imatinib mesylate is not metastable.                It is fairly stable to heat even at 120° C./6 hours.        
Table-5 shows the stability of α2 form under accelerated stress conditions (45±2° C., 75±5% RH, 6 months) in the bulk and capsule formulation
TABLE 5Stability of α2 form of Imatinib mesylate in bulk andformulated capsulePolymorph content* ofPolymorph content*imatinib mesylate inof bulkformulated capsuleimatinib mesylateDuration of storagePolymorph formPolymorph form(months) atdetecteddetected40 ± 2° C./75 ± 5% RHα2 formα2 form0 Month α2 formα2 form1 Month α2 formα2 form2 Monthsα2 formα2 form3 Monthsα2 formα2 form6 Months(XRPD FIG. - 4)*The presence of form-β was below the detection level in these examples showing that α2 form is not converted to β-form over a time period. The stability of α2 form in bulk and in the formulated capsule is thus established.
Table-6 shows comparative dissolution data of Imatinib capsule formulation containing α2 form and β-form. The formulation with α2 form is found to have better dissolution characteristics.
TABLE 6Comparative dissolution data for Imatinib mesylate capsules 100 mg*(α2 and β-forms)Test parameters1.Dissolution medium0.1 N HCl2.Dissolution volume900 ml3.RPM (Revolutions Per Minute)504.Wave length240 nm(for assay determination)Imatinib mesylateImatinib mesylate(β-crystal form)(α2 crystal form)Release profilecapsules 100 mgcapsules 100 mg 5 minutes32.6%61.3%10 minutes54.4%85.5%15 minutes69.4%90.5%20 minutes78.2%92.6%30 minutes95.8%98.0%45 minutes100.0%100.0%                The capsules contain Imatinib Mesylate equivalent of 100 mg of Imatinib base. The excipients are as per the Example-7        
Inference: The release profile and dissolution data show that the capsule formulation with α2-form is better than the formulation with β-form.
Storage of capsule containing pure Imatinib mesylate α2 form prepared by the process of the present invention at about 40° C. and about 75% relative humidity for 6 months, does not show any significant conversion to β-polymorphic form of Imatinib mesylate preferably less than about 5%. The detection of Imatinib mesylate form-β in a pharmaceutical formulation to the extent about 1% w/w or more may be accomplished by use of x-ray powder diffraction.
The pharmaceutical formulations containing the novel, stable α2 form prepared by the process of the present invention are useful in the treatment of Chronic Myelogenous Leukemia. The oral pharmaceutical dosage forms preferably contain about 100 mg of the base equivalent.
The preparative aspects, physical and functional properties of novel Imatinib mesylate α2 form prepared by the process of the present invention are compared with the properties of α form described in the prior art (WO 99/03854) and tabulated in Table-7. The tabulated data clearly demonstrates the stability and functional superiority of the novel α2 polymorph of the present invention over the α polymorph described in WO 99/03854.
TABLE 7A COMPARATIVE ACCOUNT OF IMATINIB MESYLATE α-FORMKNOWN IN PRIOR ART AND THE NOVEL α2 FORM OF CURRENTINVENTIONLiterature α formPresent inventionS. No.PropertyWO 99/03854α2 form1.Method ofPreparation reported inThe method results in novel andpreparationethanol solvent. Howeverstable α2 form consistently inmethod not reproduciblehigh purity and yield.yielding β-form only2.Melting point226° C.223-227° C.3.Differential scanning226° C. (start of melting)225-227° C. Peak 227°thermogram4.XRDSpectrum scan given 2θSpectra given in FIGS. 1& 4values not listedPrincipal 2θ values 4.9, 10.4,14.9, 16.4, 17.6, 18.6, 19.1,21.2, 24.6, 24.9, 28.55.Crystal shapeNeedle shape (Not freeNon-needle shaped free-flowingflowing)crystals6.HygroscopicityHygroscopicNon-hygroscopic7.DissolutionNot mentionedDissolves freely in watercharacteristicDissolution of more than 95%during 30 min in capsuleformulation8.Flow propertiesNot well-suited toFound to be well suited forpharmaceutical solidpharmaceutical formulations asdosage formssolid dosage forms.9.StabilityMetastable at roomStable at room temperature andtemperatureeven at 120° C.
The details of the invention are provided in the Examples given below which are provided to illustrate the invention only and therefore they should not be construed to limit the scope of the invention.